OBJECTIVE This study explored whether activation of the receptor for advanced glycation end products (RAGE) is implicated in the development of diabetes complications. RESEARCH DESIGN AND METHODS A case-cohort study was performed in 3,763 participants with prevalent diabetes in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. The hazard ratios (HRs) for death,major cardiovascular events, and new or worsening nephropathy were derived using Cox regression models, and the ability of sRAGE and AGE levels to reclassify the risk of nephropathy was assessed. RESULTS After adjustment for a range of possible confounders and other risk factors, sRAGE levels were associated with all-cause mortality (HR 1.11 for a 1-SD increase of log sRAGE [95% CI 1.00-1.22]; P = 0.045) and new or worsening nephropathy (HR 1.20 for a 1-SD increase of log sRAGE [95% CI 1.02-1.41]; P = 0.032). Circulating AGE levels were also independently associated with new or worsening nephropathy (HR 1.21 for a 1-SD increase [95% CI 1.08-1.36]; P = 0.001). Both markers also significantly improved the accuracy with which the 5-year risk of new or worsening nephropathy could be predicted (net reclassification index in continuous model, 0.25 for sRAGE and 0.24 for AGE levels). CONCLUSIONS In adults with type 2 diabetes, increased levels of sRAGE are independently associated with new or worsening kidney disease and mortality over the next 5 years. Higher levels of AGE are also associated with an increased risk of adverse renal outcomes. The AGE/RAGE axis may be of importance in the prevention and management of diabetes complications.